Identification Of Risk Loci Associated Witji Prostate Cancer In Chinese Men

Prostate cancer(PCa) is one of the most common malignant tumors in the male urinary system in the world. The carcinogenesis of PCa is a process that involved in multiple factors, multiple genes and multiple steps and it is induced by genetic and environment factors. Genetically, single nucleotide polymorphism(SNP) plays an important role in the occurrence and development of PCa. Recent studies have found that SNP can not only predict the risk of PCa, but also play a role in predicting the outcome of PCa patients. With widely use of GWAS, multiple SNPs associated with PCa were found, mainly located at 2q, 8q, 11 p, 19 q, 17 q and 22 q. While more than 70 prostate cancer predisposition loci have been identified, majority is mainly from the European ancestors. The GWAS which performed in low PCa risk populations showed that population specific risk loci might exist. Because of the different genetic background from western countries, identifying the predisposition loci in the Chinese population, where prostate cancer incidence is relatively low, may help not only to study the molecular and genetic mechanism, but also to understand the reason of different incidence by comparing the population differences. The collagen gene family encodes collagens which are extracellular matrix molecules used by cells for structural integrity and it includes 28 different collagen types. Collagen plays an important role in the occurrence and development of cancer, is involved in the regulation of cell proliferation, metastasis, differentiation and apoptosis, which can promote the invasion and metastasis of prostate cancer cells. COL28A1 encodes a novel protein, belonging to the class of von Willebrand factor A(VWA) domain-containing proteins, whose biological function has not been reported in prostate cancer. The VWA domains usually play a role in cell adhesion and migration. In summary, it is significant to study the SNPs of COL28A1 gene in prostate cancer for understanding the specific SNPs in Chinese population.Objective: The study was aimed to identify the specific prostate cancer susceptibility alleles in the Chinese population. Identifying the predisposition loci of COL28A1 gene in the Chinese population and study their functions in the occurrence and development of PCa for providing important basis for understanding the pathogenesis of prostate cancer in low risk population.Methods: To identify common prostate cancer susceptibility alleles in the Chinese population, we genotyped 211,155 SNPs on a custom i COGS array in blood DNA from 495 cases and 640 controls and evaluated the nominally associated loci in another cohort of 814 cases and 1487 controls through Taq Man quantitative PCR. Then we used DNA samples taken from 60 randomly selected healthy Han Chinese to resequence the promoter, 5’UTR and 3’UTR region of COL28A1 gene and then genotyped three selected SNPs in the training cohort. SPSS18.0 was used to analyze the data. Chisquare test was used to determine the associations between SNPs and the risk of PCa by calculating odds ratios(ORs) and 95% confidence intervals(CIs). The e QTL was applied to assess the effect of the genotype on gene expressionResults: 1. Five new loci associated with PCa were identified in the Chinese population through the custom i COGS array, then we genotyped the five SNPs in a training cohort and found that rs10235505 [A] was associated with the increased risk of PCa(OR=1.189,95%CI=1.052-1.343) and rs12567052 [A](OR=0.836, 95%CI=0.737-0.947) was a protective factor of PCa.2. We detected the expression of the nearest genes of these two loci, KIF14 and COL28A1. The risk allele rs10235505 [A]was significantly(P=0.0095) associated with a higher COL28A1 expression than the allele [G] in the Chinese(n=107)but not UK(n=96) prostate tissues.3. We found four SNPs, rs4720739(13.4%), rs79808090(15.4%), rs76674714(16.4%) and rs7925534(3.4%) in the promoter region of COL28A1 with the sanger sequencing.4. There were no statistically significant differences between rs4720739, rs79808090 and rs76674714 with the risk of PCa. rs76674714 [C](OR=0.566,95%CI= 0.364-0.879) was significantly associated with low levels of PSA(PSA<50 ng/ml vs 50 ng/ml).Conclusions: 1. rs10235505 and rs12567052 are the specific prostate cancer predisposition loci in the Chinese population.2. Patients with rs10235505 AA genotype and allele A are associated with the increased risk of PCa and rs12567052 AA genotype and allele A are protective factors of PCa.3. rs10235505 [A] may increase prostate cancer risk by affecting cell migration/invasion through influencing COL28A1 expression in the Chinese4. The SNPs located in the promoter region of COL28A1, rs4720739, rs79808090 and rs76674714 have no statistically significant correlation with prostate cancer. The rs76674714 [C] is significantly associated with low levels of PSA.